OBJECTIVE: To evaluate the cost-effectiveness of recombinant human hyaluronidase-facilitated subcutaneous (rHFSC) fluid administration compared to intravenous (IV) fluid administration in children with mild to moderate dehydration in the emergency department (ED). METHODS: A decision analytic model was created based on the results of a controlled clinical trial that compared the administration of isotonic fluids via rHFSC or IV for rehydration. The costs were determined from the hospital’s perspective. The effectiveness unit was successful rehydration in the ED without the need for hospitalization for continued hydration. Mean estimates were determined for both the cost and effectiveness of each treatment. The incremental differences in costs and effectiveness were determined between treatments. Sensitivity analysis testing was also conducted. RESULTS: The treatment success rate was 93% with rHFSC fluids and 76% for IV fluids. Across all ages, the mean cost of rHFSC fluids was $722, compared to $889 for IV fluids. The difference in effectiveness was due to the larger number of patients for whom IV access could not be established, necessitating a rescue route of administration to deliver parenteral fluids. The difference in the overall cost was primarily due to the shorter time in the ED for patients receiving rHFSC fluids versus those treated with IV fluids. The cost-effectiveness of rHFSC compared to IV was most apparent in younger patients (<3 years of age), where IV access was more difficult to obtain. CONCLUSION: Analysis of this clinical trial data revealed that rHFSC fluid administration demonstrated greater treatment effectiveness and cost-effectiveness than traditional IV fluid administration in the ED. The primary reasons for this were the ease of obtaining parenteral access via rHFSC in young patients (especially those under 3) where IV access is difficult, and a shorter ED stay with rHFSC fluid administration.